It is generally accepted that the endocrine renin-angiotensin system (RAS) serves an important role in the homeostatic response to alterations in cardiovascular function. Recently, local renin-angiotensin systems have been demonstrated in the blood vessel, kidney, and other tissues; however little is known regarding the regulation or function of these systems in the normal state. The contribution of tissue (especially vascular and renal) RAS to disease states is also undefined. Of particular interest is chronic experimental heart failure in the rat. Our preliminary data have demonstrated that tissue RAS is activated, while circulating RAS is normal in these animals. In addition Pfeffer et al have demonstrated that ACE inhibition prevents cardiac dilatation and improves survival. Accordingly, the specific aims of this application are: (1) to compare the regulation of the circulating and tissue RAS systems in normal Sprague-Dawley rats. The effects of sodium balance, beta-adrenergic activity, and circulating neurohormones on vascular and renal RAS will be determined; (2) to determine whether tissue and plasma RAS activities are altered in experimental heart failure produced by coronary ligation in the rat. The effects of disease severity (MI size) and chronicity will be examined; (3) to determine the pathophysiologic role of vascular RAS in experimental heart failure by examining the relationship of vascular RAS activity to vascular compliance, vascular reactivity, and vascular structure in conduit and resistance vessels; and (4) to elucidate the pathophysiologic role of renal RAS in experimental heart failure by studying the relationship of its activity to renal blood flow, glomerular filtration rate, and sodium balance. The effects of ACE inhibition and its withdrawal on vascular and renal functions in vivo, ex vivo, and in vitro will provide further information on the roles of these local systems. Increased vascular AII is expected to elicit vascular remodeling, decreased compliance and decreased vascular reactivity. Increased intrarenal AII is hypothesized to increase sodium avidity and plasma volume. It is our hypothesis that vascular and renal tissue RAS in chronic heart failure may contribute to progressive left ventricular dilatation by increasing afterload and preload, respectively. These investigations should provide novel information on the physiological and pathologic roles of circulating and tissue RAS activity.